1. Field of the Invention
The present invention relates generally to the treatment of diseases characterized by defective chloride transport, including cystic fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and other inflammatory disorders of the airways, intestinal constipation, pancreatitis, and dry eye syndrome. The invention is more particularly related to compositions comprising one or more compounds such as flavones and/or isoflavones, and/or vitamin C and related compounds, which may be used to activate chloride transport (i.e., absorption and/or secretion) in epithelial tissues of the airways, the intestine, the pancreas and other exocrine glands.
2. Description of the Related Art
Cystic fibrosis is a lethal genetic disease afflicting approximately 30,000 individuals in the United States. Approximately 1 in 2500 Caucasians is born with the disease, making it the most common lethal, recessively inherited disease in that population.
Cystic fibrosis affects the secretory epithelia of a variety of tissues, altering the transport of water, salt and other solutes into and out of the blood stream. In particular, the ability of epithelial cells in the airways, liver, pancreas, small intestine, reproductive tract and other tissues to transport chloride ions, and accompanying sodium and water, is severely reduced in cystic fibrosis patients, resulting in respiratory, pancreatic and intestinal ailments. The principle clinical manifestation of cystic fibrosis is the resulting respiratory disease, characterized by airway obstruction due to the presence of thick mucus that is difficult to clear from airway surfaces. This thickened airway liquid contributes to recurrent bacterial infections and progressively impairs respiration, eventually resulting in death.
In cystic fibrosis, defective chloride transport is generally due to a mutation in a chloride channel known as the cystic fibrosis transmembrane conductance regulator (CFTR; see Riordan et al., Science 245:1066-73, 1989). CFTR is a linear chloride channel found in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase. Many mutations of CFTR have been reported, the most common of which is a deletion of phenylalanine at position 508 (ΔF508-CFTR), which is present in approximately 70% of patients with cystic fibrosis. A glycine to aspartate substitution at position 551 (G551D-CFTR) occurs in approximately 1% of cystic fibrosis patients.
Current treatments for cystic fibrosis generally focus on controlling infection through antibiotic therapy and promoting mucus clearance by use of postural drainage and chest percussion. However, even with such treatments, frequent hospitalization is often required as the disease progresses. New therapies designed to increase chloride ion conductance in airway epithelial cells have been proposed, but their long term beneficial effects have not been established and such therapies are not presently available to patients.
Hypersecretion of sticky mucus by the airways is a hallmark of inflammatory airway diseases, such as asthma, chronic bronchitis and COPD (chronic obstructive airway disease). Asthma is currently a worldwide problem, with increasing prevalence in both children and adults. Total prevalence is estimated to be 7.2% of the world's population (6% in adults, 10% in children). However, there can be wide variation between the prevalence of asthma in different countries and even within different areas of a country. About 20 million Americans report having asthma with more than 70% of people with asthma also suffering from allergies. Sixty percent of people with asthma suffer specifically from allergic asthma. In 1999, it was estimated that 24.7 million Americans have been diagnosed with asthma in their lifetime. Over six million children under 18 report having asthma.
Chronic bronchitis and COPD are commonly found in long-term smokers where excessive mucus secretions and poor mucociliary clearance cause recurring airway inflammation and destruction of the airway epithelium. Current treatment effects are limited and the prognosis of airway disease in long-term smokers is poor.
Accordingly, improvements are needed in the treatment of diseases characterized by defective chloride transport, such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, and other inflammatory disorders of the airways, intestinal constipation, pancreatitis, and dry eye syndrome. The present invention fulfills this need and further provides other related advantages.